Our long-term objective is to provide data and insights that can maximize the cariostatic benefits of fluoride with the minimum degree of adverse side effects. Previous studies have shown that the fluoride levels of the oral fluids and the developing enamel are functions of plasma fluoride levels as are the development and severity of enamel fluorosis and the degree of cariostasis. Hence, several studies on factors that may influence plasma and other tissue fluoride levels are proposed. Physiologic variables that may be responsible for the observed circadian rhythm in plasma fluoride levels will be examined in dogs and rats. These include cyclic variations in the soft tissue distribution of fluoride, the magnitude of extra-to-intracellular pH gradients, the trapping of fluoride in the alkaline environment of secreting parietal cells and duodenum, and the renal handling of fluoride. There are indications that the fractional retention (balance) of fluoride may be influenced by the dose size and frequency. This possibility will be examined in acute studies with dogs and chronic studies with rats. A study with five species of laboratory animals to quantitatively compare the major features of fluoride metabolism and the ionic compositions of saliva will be done. This information will provide a data base for the selection of appropriate animal models in future studies. As an extension of continuing studies with rodents, the cariostatic efficacy of systematically derived fluoride will be compared to orally administered fluoride. Correlations between caries scores and Streptococcus mutans counts will be determined. Efforts will be made to determine when the developing molar enamel of rats is susceptible to fluorosis. When the molar enamel is in discrete developmental stages, single fluoride doses will be given. After eruption, the teeth will be examined microradiographically for evidence of fluorosis. In the clinical dental setting or among patients taking high doses of fluoride for the treatment of osteoporosis, epigastric distress may be a limiting side effect. Therefore, the effects of sodium fluoride and of MEP at different concentrations in neutral or acidic solutions on rat gastric mucosal blood flow and structure will be determined. In related studies with dogs, portal and hepatic vein fluoride and enzymatic concentrations will be determined after the intragastric administration of fluoride ion or MFP. These studies should contribute to our understanding of the metabolism, toxicity and cariostatic mechanism of fluoride.